Basic esters of 1-aryl-cyclopentene-(3)-1-carboxylic acids



Patented Get. 30, 1951 BASIC ESTERS OF l-ABYL-CYCLOPENTENE- (3)-1-CAR.BOXYLIC ACIDS Franz Biiiiger, Basel, and Rolf Denss, Zurich, Switzerland, assignors to J. R. Geizy A. G.,'

Basel, Switzerland No Drawing.

Application November 4, 1948, Se-

rial No. 58,358. In Switzerland December 24,

6 Claims. 1 The present invention is concerned with new basic esters and amides of i-aryl-cyclopentene- (3) -1-carbonlic acids, having the general forand their salts, as well as the l-aryl-cyclopentene-(3) -1-nitriles serving as intermediate products.

In the above formula and in those which follow- R1 and R: each stand for a hydrogen atom, a halogen atom, a methyl or methoxy group or R1 and R: joined together stand for a trior tein'amethylene chain. Radicals corresponding to the definition of are thus, for example: phenyl; 2-, 3- and 4- methyl-phenyl; 3,4-, 2,4- and 2,5-dimethylphenyl as well as other isomers; tetralyl-S and -6; indanyl-S; 4-cl1lorophenyl; 3,4-dibromophenyl; 2-, 3- and 4-methoxy-phenyl; 3,4-dimethoxy-phenyl and isomers; 3-methyl4- methoxy-phenyl and isomers; 4-isopropoxyphenyl; I z-ethoxy-phenyl,

X stands for an oxygen atom, an imino, methylimino or ethylimino group n standsfor a .whole number between 2 and 6 inclusive; thus 'C)|H2nstands for a bivalent, aliphatic hydrocarbon radical, e. g.,

Am stands for the radical of a non-aromatic, secondary amine. In particular, Am includes the radicals t I BIG and where R and R' each stand for a lower allwl radical,

preferably containing 1-2 carbon atoms,

R stands for a bivalent aliphatic radical, which can also contain an oxygen atom as a chain member, has preferably 4 or 5 members in the chain and contains 4 to 6 carbon atoms. Radicals corresponding to this definition of Am are. for example, tho 3 derived by removal of the hydrogen atom bound to the nitrogen atom of dimethyl-, diethyl-, dipropy1-, di-isopropyl-, di-allyl-, methyl-ethylor methylpropylamine, piperidine, pyrrolidine or morpholine.

Benzyl cyanide has been converted to l-phenyl-cyclopentane-l-nitrile by the interaction of 1,4-dibromo-butane and sodium amide and the nitrile then hydrolysed to give l-phem'l-cyclo- -pentane-1carboxylic acid (F. H. Case, J. of Am.

Chem. 800., 1934, 56, 715). Likewise, it is known how to prepare basic esters and amides of 1-arylcyclopentane1-carbo1wlic acids (U. S. Patents 2,404,588 and 2,437,545).

However, corresponding derivatives of a 1- aryl-cyclopentene-i-carboiwlic acid have been unknown up till now. It was also unexpected to find that l-aryl-cyclopentene-(Zi)-1-nitriles can be prepared from arylacetonitriles and 1,4- dihalogen-butene-2, since it is known that 1,4-dlhalogen-butene-2 is not suitable for ringclosure.

The surprising discovery has now been made that 1,4-dihalogenbute'ne-2 can be successfully condensed with arylacetonitriles to give l-arylcyclopentene-( 3) -l-nitriles.

The condensation is carried out in the presence of an agent which splits ofl hydrogen halide. It is preferable to use those agents which can form a metal derivative of the arylacetonitrile. Generally, there come into consideration: alkali metals and active alkali compounds, such as sodium amide, potassium amide, phenyl sodium, phenyl lithium and potassiumtert. butylate. The reaction takes place under very mild conditions with finely divided sodium amide, so that we prefer to use it, not only because of this advantage but alsobecause of its low price.

A preferred method of carrying out the process consists in gradually mixing a solution of approximately equimolecular quantities of 1,4-dihalogen-butene-2 and of arylacetonitrile in an inert solvent such as benzene or ether, at about 0 C. with roughly two mols of finely divided sodium amide.

It is advantageous to use 1,4-dichloroor 1,4- dibromobutene as 1,4-dlhalogen-butene-2. As second component any arylacetonitrile comes into consideration, as long as it does not con tain substituents which, themselves react with 1,4-dihalogen-butene-2 and sodium amide. It

is preferred to use arylacetonitriles corresponding to the formula.

The 1-aryl-cyclopentene-(3)-1-nitriles obtained can be hydrolysed to give the corresponding carboxylic acids. For this purpose it is advantageous to heat the nitriles with an alcoholic or aqueous alcoholic solution of an alkali hydroxide in a closed vessel at about 150 C.

@c-oo v z-cnah-am v I II III Y and Z denote radicals which split oil in the reaction with the exception of a bivalent radical --NH-, or N(alkyl)- contained in either one of them.

In accordance with the above, for example, a 1-aryl-cyclopentene-(3)-l-carboxylic acid (II. Y=OH) or (usually with more advantage) its reactional functional derivatives, such as acid halides, acid anhydrides, alkyl and aryl esters (II, Y=halogen,

OCOalkyl, -O-alkyl, --Oaryl and so on) can be reacted with an amino alcohol (HI, Z=OH). The named reactive carboxylic acid derivatives can also be reacted with a metal compound of the amino alcohol (III, Z=O-Met, Met means a normal equivalent of a metal capable of forming an alcoholate, such as Na, K. Mg, Al and so on).

In all these cases the basic esters are obtained. In an analogous manner the basic amides are obtained when the carboxylic acids (II, Y=OH) or the functional derivatives thereof already mentioned are reacted with a diamine (III, Z=H2N- or HN(alkyl)-).

A preferred method of carrying out the manufacture, which method is of general application, consists in bringing together l-aryl-cyclopentene- (3)-l-carboxylic acid chloride (II, Y=Cl) with double the molecular quantity of amino-alcohol or diamine (III, Z=HO, HzN or HN-(alkyl)) in an inert solvent, such as benzene. Reaction takes place even at room temperature; however, after the reaction has died down, it should be brought to completion by heating the mixture. If only one mol of amino alcohol or of diamine is used, then this method gives the hydrochloride of the basic ester or amide directly. its purity being in direct ratio to that of the starting materials.

The same compounds may also be prepared when a reactive ester of an amino-alcohol (III, e. g., Z=halosen, aryl-SO:O) is reacted with the carboxvlic acid or a salt of the same (II. Y=OH or O-cation) (formation of the basic esters) or with a metal derivative of an amide of the carboxylic acid (II, Y=NH-metal or N(alkyl) -metal, whereby the alkali metal derivatives are particularly suitable as metal derivatives) (formation of the basic amides).

For example, the hydrochloride of the basic ester is obtained when the carboxylic acid (II, Y=OH) is heated with the chloralkylamine (III, Z=Cl) in an inert solvent, such as benzene or ethyl acetate. A suitable method of preparing the basic amide consists, e. g., in converting the carboxylic acid amide (II, Y=NH: or NH-alkyl) into the sodium derivative by heating with sodium amide in an inert solvent such as toluene and then reacting the sodium derivative with the chloralkylamine (III, Z=Cl) by heating.

A further process consists in reacting a reactive ester of a 1-ary1-cyclopentene-(3) -1-carboxylic acid-oxyalkyl ester or -oxyalkyiamide, corresponding to Formula IV with a secondary, non-aromatic amine. In the above equation V stands for a reactive radical, e. g., halogen or --OSOz--aryl. If tertiary amines are used instead of secondary in this process, then the quaternary salts of the basic esters of Formula I are obtained.

The starting materials of Formula IV necessary for this process are obtained, for example, by the action 'of a 1-aryl-cyclopentene-(3)-1- carboxylic acid chloride on a compound of the formula The new esters and amides of Formula I are bases which are practically insoluble in water. They form water-soluble salts, some of which crystallise well, with inorganic and organic acids commonly used for the production of salts used in therapeutics such as, e. g., hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, lactic acid, malic acid, mucic acid, succinic acid, maleic aid, methane-sulphonic acid. ethane-disulphonic acid. Furthermore they form quaternary salts, which readily dissolve in water, on the addition of reactive esters of aliphatic and araliphatic alcohols, such as alkyl chlorides, bromides and iodides, dialkyl sulphates or aralkyl chlorides, bromides and iodides, e. g., ethyl bromide, allyl bromide, dimethyl sulphate or benzyl chloride.

The esters andamides preparable according to the present invention are intended for use as therapeutics acting on the vegetative nervous system. They have the advantage over lmown similar compounds that their salts are more stable in aqueous solution. The anti-allergic action which is also a property of the majority of new compounds, is also of interest.

The basic esters and amides of the l-aryl-cyclopentene-(3)-l-carboxylic acids as well as their salts can be converted into the corresponding derivatives of l-aryl-cyclopentane-carboxylic acids by hydrogenation under conditions usual for the hydrogenation of a double bond, e. g.,

v lysts.

" 240 parts 1? awolute 'lowed by which can in the presence of nickel or noble metal cata- Some or the more convenient ways of out the processes of the invention, as well as a number 'o'f the preferred compounds preparabie"thereby are more closely-describeddn the following examples Parts are parts fw ight unless otherwise The ratio of parts by weight to parts by volume is that oi kilograms to litres. Temperatures are in degrees eenia-igrade.

Example 1 l-pheny'l-cyclopentene-(3) -l -nitrile A suspension or 90 benzene is added in-porand cooling well, toa solution of 132 parts of benzyl cyanideand 141 parts or -lA-dichloro-butene-2 in 800 parts or absolute benzene. The reaction temperature should lie between -7 and 0. Next the-mixture isstirredfor a further 10 to h0urs at room temperature and water is then added. benzene solution is separated by means voi a separating funnel and washed in succession with 2 N sulphuric acid, 2 N caustic soda solution and with water. After drying with sodium sulphate the'solvent is distilled oil. The residue boils at 1435-1455" under 17-min. pressure and is the nitrile of the above formula.

lA-dichloro-butene-z can be made from butene-diol by saturating with hydrogen chloride at 50, separating oil the water formed. w with 2 N caustic soda and then with water, foldrying anddistillation. Its B. P. is 145-147.

Instead otl-A dichloro-butene-a the-equivalent amount 0f IA-dibromo-butened may also be used.

Absolute ether or toluene can be used instead or b'enzene as solvent.

The -following are examples oi compounds be prepared as described ill-Example 1: General formula parts oi anemia,

'8 E mmple2 l-phenyl-cyclopentene- (3) -l-carboxylic acid COOK Amiis filtered, 10o parts'foi' wam: methanol distilled 'dii"on the watei'- bath. next th'eresidixe a seemed with .9 ydrochloric aeid; c'r'ii'de l-'-Pheny' l=eyo1opei1tene1(3=).-i+ar bonus acid which preeipitate'sout' is alter d or undersuction"and washed with distilled water until the wash-water reacts to; litmus.

The acid, from melts at mil-129. Sodium hydroxide may also be-used, instead of potassium hydroxide.- The following are ex- *axhples ot-acidswhich can be as described -}2 above:

General formula an ethanoFwater coon R;

Example 3 1-phenyl-cyclopentene(3) -1-'ea'rbo:'r'ylic acidp-diethylammo-e't-liyl ester hydrochloride COOCHaCHaN HCl can 76 boils at 118-120" 9.80 parts of.1 -phenyl-cyclopentene-(3) -1-car- =boxyllc acid are boiled-tor 12'liours' under reflux -with 1 3.4 0 parts of fi-diethyla'mino-etliyl chloridedrochloride and 20 parts'oi anliydrous potassium carbonate in 40 parts of ethyl acetate. After cooling, water is added, the mixture separated in the'separatin'g i'un'nel'and-the ethyl acetatesolutio'n extracted several timeswith 2 N hydrochloric acid. The is I separated from the lumped hydrochloric-acid extracts by treatment with 10% caustic sodasblut'ion,takenupinether and the ethereal solution dried with sulphate. The oil remainingatte'r distilling oil the ether under 0.1 mm. pressureand is added. The hydrochloride is then filtered ofl undersuction. After recrystallisation from an ethyl acetate-methanol mixture it melts at 163-164. The hydrochloride of the above-mentioned hydrogenation product melts at 143-144.

Example 4 l-phenyl-cyclopentene- 3) -1-carboxylic acidp-diethylamino-ethylamide-hydrochloride 12.14 parts of l-phenyl-cyclopentene-(B) -1- carboxylic acid chloride (B. P. 73-74 under 0.17 mm. pressure, prepared from the corresponding acid by treating with thionyl chloride) dissolved in 50 parts of absolute benzene are added to 7.50 parts of N,N diethyl-ethylenediamine in 50 parts of absolute benzene, while cooling with ice. The mixture is then heated to boiling until the reaction is over (about /z hour), cooled with ice and 10% caustic soda solution added. The reaction mixture is extracted with ether and the ethereal solution washed with water. Next the basic portions of the extract are removed by treatment with 2 N hydrochloric acid. The hydrochloric acid extract is made alkaline with 10% caustic soda solution and shaken up with ether. The ethereal solution is dried with sodium sulphate and evaporated down. The oil which remains boils at 143 to 145 under 0.15 mm. pressure and is the required base. The hydrochloride of this base, prepared by the process described in Example 3, melts at 145-147.

Compounds disubstituted in the amido group can also be .prepared by the above process. When a secondary-tertiary amine is used instead of r primary-tertiary one however, the reaction takes place rather more slowly so that it is necessary to heat for a longer time (4 to 8 times as long).

Example 4.32 parts of l-phenyl-cyclopentene-(3)-1- carboxylic acid ethyl ester are heated, while exeluding moisture, with 23.4 parts of anhydrous p-diethylamino-ethanol and 0.46 part of metallic sodium for two hours in the oilbath at 140-150 (oilbath temperature). The excess p-diethylaminoethanol and the ethyl alcohol formed are distilled oil. in vacuo and, when cold, the residue is taken up in ether. The ethereal solution is extracted with 2 N hydrochloric acid. The base is freed from the lumped hydrochloric acid extracts by adding 10% caustic soda solution, taken up in ether and the ethereal solution dried with sodium sulphate. After the other has been distilled off ethyl ester. The melting point of the hydrochloride is 164-165.

Example 6 1-(3',4'-dimethyl-phenyl) -cyclopentene-(3) -1- carboxylic acid-e-diethylaminoamyl-ester.

C111: on cooiwnom CzHl 10.5 parts of the dry potassium salt of l-(3',4'- dimethyl-phenyl) -cyclopentene-(3) -1-carboxylic acid (prepared by evaporating down a solution of 12 parts of the acid in 26.6 parts of 11.7% methyl alcoholic potassium hydroxide solution in vacuo.

rubbing up the residue with acetone and filtering under suction) are heated for 15 hours at -100 with parts of 1,5-dibromopentane. After cooling, the reaction mixture is shaken with ether and water, the separated ethereal solution is washed thrice more with water and dried with sodium sulphate. After distilling oil the ether the residue is fractionated in vacuo. The boiling point of the product is 172176 under 0.45 mm. pressure.

The greater part of the excess 1,5-dibromopentane is recovered in the first part of the distillate.

In a similar manner may be prepared the e-blO- mo-amyl ester of l-phenyl-cyclopentene-(Zi) l-carboxylic acid which boil at 135-l41 under 0.09 mm. pressure. Further, on using 1,4-dibromobutane instead 1,5-dibromo-pentane the prodnot is the a-bromo-butyl ester of l-phenyl-cyclopentene-(S) -(1) -carboxylic acid. It boils at 127- 140 under 0.18 mm. pressure.

13 parts of the e-bromo-amyl-ester of 1-(3',4'- dimethyl-phenyl) -cyclopentene- (3) -l-carboxylic acid are heated with 13 parts of diethylamine in parts by volume of absolute benzene for 6 hours in an autoclave at 100-110. The benzene solution is then washed three times with water and 3 times with 2 N hydrochloric acid. The joint extracts are washed with ether and then made alkaline with 30% caustic soda solution, while cooling with ice. The bases are then extracted with ether and the residue, after distilling oflf the ether, is fractionated in vacuo. The product is 1-(3,4'-dimethylphenyl) cyclopentene (3)-1- carboxylic acid-e-diethylamino-amyl ester, boiling at 164-165 under 0.19 mm. pressure. The melting point of the hydrochloride (after recrystallising from a mixture of ethyl acetate and methanol) is 124-125.

In a similar manner may be prepared the -di ethylamino-amyl ester of l-phenyl-cyclopentene- (3)-1-carboxylic acid (B. P. 149150 under 0.22 mm. presure, M. P. of hydrochloride 7375) and the a-dimethyl-amino-butyl ester of l-phenylcyclopentene (3) 1 carboxylic acid (B. P. -125 under 0.1 mm. pressure. M. P. of hydrochloride Ill-112).

The following basic esters and amides may also be prepared by the methods given in the above examples and in the description:

General formula cicoo c.Hh-Am ethyl- (p-morphollno-ethyl) -amide, l-phenyl cyc1opentene-(3) -1-carboxyllc acidmethyl-(y-piperldino-propyl) -amide, 1-(4'-chloro-phenyl) cyclopentene (3) -1-carbonlic acid-p-diethybMo-ethyl-amlde, 1-(3',4'-dimethyl-phenyl) cyclopentene-(3)-1- carboxylie acid-7 dimethyl amino propylamide, 1-(4' methoxy phenyD-cyclopentene (3)-1- carboxyllc acid-'y-diethyl-ammo-propylamide, 1-(3'-methyl 4'-methoxy phenyl) -cyc1opentene-(3) -1-carboxyllc acid-ethyl (B-diethylamino-ethyl) -amide,

1-lndanyl-(5') -cyc1opentene (3) -1 carboxylic acid-methyl- (fi-dlmethylamino ethyl) -am1de. What we claim is: 1. A compound of the formula wherein R1 and R: each represents a member selected from the group consisting of a hydrogen atom, a halogen ,atom, a methyl and a methoxy group and, joined together, a, trfmethylene and a tetramethylene radical, n represents an integer from 2 to 6, and Am represents a member selected from the group consisting of a di-(lower-alkyD- amino, a morphollno and a piperidlno radical.

2. The compound of the formula 3. The compound of the formula 14.2.0! No. 3. R, 1: 0,11,, Am 111*. n (11 U p-CHa..- m-CHL. -N-- do do 144445 0.12 7-118 cm I ao....- oem. n.-- -Nnan -N/ mm 0.2 141-148 CE. I 40 an n -N crm,- 141-140 0.05 hygro- 43H: CIH w 41-.--. p-Cl n N CHr-CH: M 151-101 0.: .do

a (CH; a(m,p)-NH M 104-106 0.11 m-m Further compounds which may be prepared as 4. The compound of the formula described herelnbefore are, e. g., 25 1-(4'chloro-phenyl) cyc1opentene-(3)-1-carboxylic acid-f-dimethylamino-henl ester, Z 51 45) cyclopentene (3)-1-carbo1w1ic C CH: cm-o acld-p-(methylwthyl-amino) -ethyl ester, H: H 1-indanyl-(5') -cyclopentene (3) 1 carboxylic 30 methyl ammmbutfl ester. 5. The compound of the formula l-phenyl-cyclopentene (3) -1 carboxylic acid- CaHl 6. The compound of the formula CH: Q04: O0(CH1):N/

CE: \CH1 CH1 FRANZ nlimam ROLF DENBS.

REFERENCES CITED The following references are of record in the file of this patent:

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1. A COMPOUND OF THE FORMULA 